INTRODUCTION
Fatigue occurs most often as part of a symptom complex, but even when it is the sole or main presenting symptom, fatigue is one of the most common symptoms.
Fatigue is difficulty initiating and sustaining activity due to a lack of energy and accompanied by a desire to rest. Fatigue is normal after physical exertion, prolonged stress, and sleep deprivation.
Patients may refer to certain other symptoms as fatigue; differentiating between them and fatigue is usually, but not always, possible with detailed questioning.
Weakness, a symptom of nervous system or muscle disorders, is insufficient force of muscular contraction at maximum effort. Disorders such as myasthenia gravis and Eaton-Lambert syndrome can cause weakness that worsens with activity, simulating fatigue.
Dyspnea on exertion, an early symptom of cardiac and pulmonary disorders, can decrease exercise tolerance, simulating fatigue. Respiratory symptoms usually can be elicited upon careful questioning or develop subsequently.
Somnolence, a symptom of disorders causing sleep deprivation (eg, allergic rhinitis, esophageal reflux, painful musculoskeletal disorders, sleep apnea, severe chronic disorders), is an unusually strong desire to sleep. Yawning and lapsing into sleep during daytime hours are common. Patients can usually tell the difference between somnolence and fatigue. However, deprivation of deep non rapid eye movement sleep can cause muscle aches and fatigue, and many patients with fatigue have disturbed sleep, so differentiating between fatigue and somnolence may be difficult.
Fatigue can be classified in various temporal categories, such as the following:
Recent fatigue: < 1 month duration
Prolonged fatigue: 1 to 6 months duration
Chronic fatigue: > 6 months duration.
Chronic fatigue syndrome is one cause of chronic fatigue. There are now 2 other terms for chronic fatigue syndrome—myalgic encephalomyelitis and systemic exertion intolerance—although there is no clear delineation between these at this time. Patients with COVID-19 may have symptoms that last for weeks or even months, which is known as “long COVID” or “long-haul COVID” and resembles postviral fatigue (and can be called post-viral fatigue syndrome) and chronic fatigue syndrome.
Chronic fatigue syndrome (CFS, also called myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]) is a syndrome of life-altering fatigue lasting > 6 months that is unexplained and is accompanied by a number of associated symptoms. Management includes validating the patient’s disability, treating specific symptoms, and in some patients cognitive-behavioral therapy and a graded exercise program.
Although as many as 25% of people in the United States report being chronically fatigued, only about 0.5% of people meet criteria for having CFS. Although the term CFS was first used in 1988, the disorder has been well described since at least the mid 1700s but has had different names (eg, febricula, neurasthenia, chronic brucellosis, effort syndrome). CFS is most described among young and middle-aged women but has been noted in all ages, including children, and in both sexes.
CFS is not malingering (intentional feigning of symptoms). CFS does share many features with fibromyalgia, such as sleep disorders, mental cloudiness, fatigue, pain, and exacerbation of symptoms with activity.
Etiology of Chronic Fatigue Syndrome
Etiology of CFS is unknown. No infectious, hormonal, immunologic, or psychiatric cause has been established. Among the many proposed infectious causes, Epstein-Barr virus, Lyme disease, candidiasis, and cytomegalovirus have been proven not to cause CFS. Similarly, there are no allergic markers and no immunosuppression.
Some people who have recovered from COVID-19 infection have become “long-haulers” with persistent symptoms. Some of these symptoms result from organ damage from the infection and/or treatment, and others may be from posttraumatic stress disorder (PTSD). In addition, in some patients COVID-19 seems to trigger typical CFS, but further study is needed to confirm this association and determine causality.
Various minor immunologic abnormalities have been reported. These abnormalities include low levels of IgG, abnormal IgG, decreased lymphocytic proliferation, low interferon-gamma levels in response to mitogens, poor cytotoxicity of natural killer cells, circulating autoantibodies and immune complexes, and many other immunologic findings. However, none provide adequate sensitivity and specificity for defining CFS. They do, however, underscore the physiologic legitimacy of CFS.
Relatives of patients with CFS have an increased risk of developing the syndrome, suggesting a genetic component or common environmental exposure. Recent studies have identified some genetic markers that might predispose to CFS. Some researchers believe the etiology will eventually be shown to be multifactorial, including a genetic predisposition, and exposure to microbes, toxins, and other physical and/or emotional trauma.
Symptoms and Signs of Chronic Fatigue Syndrome
Before onset of CFS, most patients are highly functioning and successful.
Onset is usually abrupt, often following a psychologically or medically stressful event. Many patients report an initial viral-like illness with swollen lymph nodes, extreme fatigue, fever, and upper respiratory symptoms. The initial syndrome resolves but seems to trigger protracted severe fatigue, which interferes with daily activities and typically worsens with exertion but is alleviated poorly or not at all by rest. Patients often also have disturbances of sleep and cognition, such as memory problems, “foggy thinking,” hypersomnolence, and a feeling of having had unrefreshing sleep. Important general characteristics are diffuse pains and sleep problems.
The physical examination Is normal, with no objective signs of muscle weakness, arthritis, neuropathy, or organomegaly. However, some patients have low-grade fever, nonexudative pharyngitis, and/or palpable or tender (but not enlarged) lymph nodes.
Because patients typically appear healthy, friends, family, and even health care practitioners sometimes express skepticism about their condition, which can worsen the frustration and/or depression patients often feel about their poorly understood disorder.
Diagnosis of Chronic Fatigue Syndrome
Clinical criteria
Laboratory evaluation to exclude non-CFS disorders
The diagnosis of CFS is made by the characteristic history combined with a normal physical examination and normal laboratory test results. Any abnormal physical findings or laboratory tests must be evaluated and alternative diagnoses that cause those findings and/or the patient’s symptoms excluded before the diagnosis of CFS can be made. The case definition is often useful but should be considered an epidemiologic and research tool and in some circumstances should not be strictly applied to individual patients.
Testing is directed at any non-CFS causes suspected based on objective clinical findings. If no cause is evident or suspected, a reasonable laboratory assessment includes complete blood count and measurement of electrolytes, blood urea nitrogen, creatinine, erythrocyte sedimentation rate, and thyroid-stimulating hormone. If indicated by clinical findings, further testing in selected patients may include chest x-ray, sleep studies, and testing for adrenal insufficiency. Serologic testing for infections, antinuclear antibodies, and neuroimaging are not indicated without objective evidence of disease on examination (ie, not just subjective complaints) or on basic testing; in such situations, pretest probability is low and so the risk of false-positive results is high. This can result in incorrect diagnoses, additional unnecessary testing, and inappropriate treatments.
Prognosis for Chronic Fatigue Syndrome
Most patients with CFS improve over time though often not back to their pre-illness state. That time is typically years and improvement is often only partial. Some evidence indicates that earlier diagnosis and intervention improve the prognosis.
Treatment of Chronic Fatigue Syndrome
Acknowledgment of patient’s symptoms
Sometimes cognitive-behavioral therapy
Sometimes graded exercise, limited to avoid a setback
Drugs for depression, sleep, or pain if indicated
To provide effective care to patients with CFS, physicians must acknowledge and accept the validity of patients’ symptoms. Whatever the underlying cause, these patients are not malingerers but are suffering and strongly desire a return to their previous state of health. For successful management patients need to accept and accommodate their disability, focusing on what they can still do instead of lamenting what they cannot do.
Cognitive-behavioral therapy and a graded exercise program have been helpful in some studies but not in others (1, 2). They should be considered for patients who are willing to try them and have access to the appropriate services. Depression is common and expected in any patient with a disability. This should be treated with antidepressants and/or psychiatric referral. Sleep disturbances should be aggressively managed with relaxation techniques and improved sleep hygiene (see table Approach to Patient, Sleep Hygiene ).
If these measures are ineffective, hypnotic drugs and/or referral to a sleep specialist may be necessary. Patients with pain (usually due to a component of fibromyalgia) can be treated using a number of drugs such as pregabalin, duloxetine, amitriptyline, or gabapentin. Physical therapy is also often helpful. Treatment for orthostatic hypotension may also be helpful.
Unproven or disproven treatments, such as antivirals, immunosuppressants, elimination diets, and amalgam extractions, should be avoided
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